Differential Diagnosis of Rapid Progressive Dementia

to dementia. Although changes are non-specific (for example pleocytosis, elevated protein content, increased albumin ratio and oligoclonal immunoglobulin G [IgG] in the CSF), their presence clearly differentiates inflammatory and autoimmune diseases from neurodegenerative dementia. On the other hand, changes in the CSF proteome have been studied in various neurodegenerative disorders. The most important and best validated to date are tests for tau and phosphorylated isoforms and Aβ peptides.

Aβ1–42 levels were initially studied in CSF samples from Alzheimer’s disease patients and controls, demonstrating high potential for this

biomarker for discrimination between the two groups. However, decreased levels were later reported in other degenerative conditions

too. Aβ1–42 levels are reduced in patients with LBD and Alzheimer’s disease compared with non-demented controls32–35

patients with CJD,36 frontotemporal dementia37 hydrocephalus (NPH).38–40 as well as in and normal-pressure Our own data revealed significantly lower Aβ1–42 levels in all dementias tested compared with controls.40

High CSF tau levels were reported first in patients with Alzheimer’s disease, and later also in other conditions such as CJD.32,41

or even significantly reduced level45 Conflicting

results were obtained for frontotemporal dementia: whereas some studies reported increased CSF tau in this form of dementia,42,43 normal levels44

were observed in

others. A potential explanation for this might be the heterogeneity of the definitions of frontotemporal dementia used. Conflicting data are available also for LBD, with either increased46

or normal47–49

concentrations compared with non-demented groups. Significantly decreased tau concentrations in LBD patients compared with Alzheimer’s disease have also occasionally been reported.50,51

One study described that the total tau level in CSF from NPH patients was significantly higher than that in controls, with a correlation between tau levels and dementia or urinary incontinence.52

Our own

data demonstrated increased tau protein concentrations in CJD, Alzheimer’s disease, LBD and frontotemporal dementia, but not in NPH, while only patients with CJD dissociated significantly from the other dementias.40

Summary

The clinical symptom dementia is characterised by a variety of changes in memory, planning, orientation and processing speed. Many diseases have been described as underlying causes of dementia. Primary dementia disorders are usually of neurodegenerative origin such as Alzheimer’s disease, LBD and frontolobar degeneration.

Pre-senile dementia is defined as symptom onset before 65 years of age. An estimated 10% of all patients with dementia have this early onset. The most frequent cause, as in senile dementia, is Alzheimer’s disease. Frontolobar degeneration is more frequent at a younger age, while LBD only rarely has a pre-senile onset. In addition to neurodegenerative causes, other diseases such as autoimmune, toxic, genetic and metabolic disorders are common factors behind early-onset dementia. Some of these conditions are potentially reversible and therefore a correct diagnosis is important.

To summarise, these markers have become standard CSF tests in the routine dementia work-up. Although some data point towards a limited value of these markers in the clinical differential diagnosis between dementia entities, their specificity can be increased if they are used in a defined clinical context. Their value is high when they are used as a part of a multimodal approach together with neuropsychological test batteries and brain imaging. In addition, the determination of ratios and isoforms is helpful. The ratio

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7. 8.

The diagnostic approach to dementia includes clinical examination (looking for associated neurological or systemic symptoms), neuropsychological testing (differentiating frontal, cortical or subcortical profile) and a detailed medical history about the onset and course of symptoms. Cerebral MRI can detect specific focal atrophy, white-matter changes or other clues as to underlying disease. Positron-emission tomography and SPECT can improve diagnostic certainty. In each case, a lumbar puncture should be performed to detect inflammatory signs (infectious or autoimmune disorders), and

dementia markers, especially Aβ1–42 and tau protein, should be measured. In young-onset dementia in particular, genetic testing should be part of the diagnostic approach. n

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Scarmeas N, Brandt J, Albert M, et al., Delusions and hallucinations are associated with worse outcome in Alzheimer disease, Arch Neurol, 2005;62:1601–8.

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11. Lopez OL, Wisnieski SR, Becker JT, et al., Extrapyramidal signs in patients with probable Alzheimer disease, Arch Neurol, 1997;54:969–75.

12. Scarmeas N, Hadjigeorgiou GM, Papadimitriou A, et al.,

Motor signs during the course of Alzheimer disease, Neurology, 2004;63:975–82.

13. Wilson RS, Bennett DA, Gilley DW, et al., Progression of parkinsonism and loss of cognitive function in Alzheimer disease, Arch Neurol, 2000;57:855–60.

14. Koss E, Edland S, Fillenbaum G, et al., Clinical and neuropsychological differences between patients with earlier and later onset of Alzheimer’s disease: A CERAD analysis, Part XII, Neurology, 1996;46:136–41.

15. Karas G, Scheltens P, Rombouts S, et al., Precuneus atrophy in early-onset Alzheimer’s disease: a morphometric structural MRI study, Neuroradiology, 2007;49:967–76.

16. Frisoni GB, Pievani M, Testa C, et al., The topography of grey matter involvement in early and late onset Alzheimer’s disease, Brain, 2007;130:720–30.

17. Bigio EH, Hynan LS, Sontag E, et al., Synapse loss is

calculated from the pathological Aβ1–42 and from the less aggregating form Aβ1–40 is of considerable value in the diagnosis of Alzheimer’s disease: it has been found that ratios <1.0 are indicative of

Alzheimer’s disease. With respect to tau, its phosphorylated form at T181 has been identified as indicating hyperphosphorylation, and it is thus considered to be a disease-specific marker for Alzheimer’s disease. The ratio calculated from tau protein phosphorylated at T181 and total tau has also increased its diagnostic utility.

Recent studies on the value of tau and Aβ as potential markers for differentiation of AD from other dementias have also shown that similar results might be obtained for other dementias, too. Thus, due to their non-specificity and low discrimination levels between different neurodegenerative dementia types, the search for a CSF (or blood) biomarker is still ongoing.

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